EEIG1

Summary

EEIG1 (estrogen-induced osteoclastogenesis regulator 1, HGNC:31419) is a protein-coding gene on chromosome 9q34.11, encoding Early estrogen-induced gene 1 protein (Q5T9C2). Key component of TNFSF11/RANKL- and TNF-induced osteoclastogenesis pathways, thereby mediates bone resorption in pathological bone loss conditions.

Predicted to be involved in positive regulation of osteoclast differentiation. Predicted to be located in cytoplasm; membrane raft; and nucleus.

Source: NCBI Gene 399665 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_001035254

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31419
Approved symbol	EEIG1
Name	estrogen-induced osteoclastogenesis regulator 1
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	Eeig1, bA203J24.7, SYM-3A
Ensembl gene	ENSG00000167106
Ensembl biotype	protein_coding
OMIM	610891
Entrez	399665

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding_CDS_not_defined, 3 protein_coding, 1 retained_intron

ENST00000300434, ENST00000373084, ENST00000373095, ENST00000465821, ENST00000479828, ENST00000493175, ENST00000494606, ENST00000953235

RefSeq mRNA: 2 — MANE Select: NM_001035254 NM_001035254, NM_203305

CCDS: CCDS35150, CCDS6888

Canonical transcript exons

ENST00000373095 — 11 exons

Exon	Start	End
ENSE00001180911	127940582	127943237
ENSE00001389582	127948071	127948225
ENSE00001459518	127979992	127980989
ENSE00003469153	127948368	127948414
ENSE00003531044	127944615	127944684
ENSE00003575183	127945649	127945753
ENSE00003579819	127944777	127944898
ENSE00003580781	127950423	127950539
ENSE00003625929	127945367	127945562
ENSE00003643568	127953575	127953604
ENSE00003683255	127953805	127953925

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.4949 / max 1131.7373, expressed in 1788 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102641	29.4712	1742
102638	12.6487	1426
102642	5.8969	1639
102632	1.3338	113
102635	0.4447	104
102640	0.3845	173
102639	0.3153	160
102633	0.2959	79
102627	0.2107	110
102631	0.1752	60

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	97.72	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.10	gold quality
islet of Langerhans	UBERON:0000006	97.06	gold quality
nucleus accumbens	UBERON:0001882	96.82	gold quality
caudate nucleus	UBERON:0001873	96.77	gold quality
putamen	UBERON:0001874	96.74	gold quality
spinal cord	UBERON:0002240	96.67	gold quality
lower esophagus mucosa	UBERON:0035834	96.52	gold quality
right uterine tube	UBERON:0001302	96.41	gold quality
endometrium epithelium	UBERON:0004811	96.30	gold quality
type B pancreatic cell	CL:0000169	96.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.16	gold quality
amygdala	UBERON:0001876	95.93	gold quality
ectocervix	UBERON:0012249	95.93	gold quality
lymph node	UBERON:0000029	95.88	gold quality
endocervix	UBERON:0000458	95.86	gold quality
sural nerve	UBERON:0015488	95.85	gold quality
body of stomach	UBERON:0001161	95.82	gold quality
prefrontal cortex	UBERON:0000451	95.71	gold quality
right frontal lobe	UBERON:0002810	95.69	gold quality
vermiform appendix	UBERON:0001154	95.66	gold quality
small intestine	UBERON:0002108	95.50	gold quality
esophagus mucosa	UBERON:0002469	95.31	gold quality
corpus callosum	UBERON:0002336	95.30	gold quality
tibial nerve	UBERON:0001323	95.29	gold quality
pituitary gland	UBERON:0000007	95.20	gold quality
mucosa of stomach	UBERON:0001199	95.06	gold quality
stromal cell of endometrium	CL:0002255	95.05	gold quality
adenohypophysis	UBERON:0002196	94.97	gold quality
inferior vagus X ganglion	UBERON:0005363	94.95	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.57
E-MTAB-5061	yes	9.04
E-CURD-11	no	115.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

203 targeting EEIG1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368

Literature-anchored findings (GeneRIF, showing 3)

• A novel estrogen-responsive gene was identified and named EEIG1 for early estrogen-induced gene 1 (PMID:14605097)
• EEIG1 is a novel RANK signaling component controlling RANK-mediated osteoclast formation. (PMID:23478294)
• In this study, 2 of 8 (primary angle-closure glaucoma) PACG-associated loci were associated significantly with PACS status, the earliest stage in the angle-closure glaucoma disease course. The association of these PACG loci with PACS status suggests that these loci may confer susceptibility to a narrow angle configuration. (PMID:29310965)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	eeig1b	ENSDARG00000016866
danio_rerio	eeig1a	ENSDARG00000102566
mus_musculus	Eeig1	ENSMUSG00000039157
rattus_norvegicus	Eeig1	ENSRNOG00000050834

Paralogs (1): EEIG2 (ENSG00000162636)

Protein

Protein identifiers

Early estrogen-induced gene 1 protein — Q5T9C2 (reviewed: Q5T9C2)

All UniProt accessions (1): Q5T9C2

UniProt curated annotations — full annotation on UniProt →

Function. Key component of TNFSF11/RANKL- and TNF-induced osteoclastogenesis pathways, thereby mediates bone resorption in pathological bone loss conditions. Required for TNFSF11/RANKL-induced osteoclastogenesis via its interaction with TNFRSF11A/RANK, thereby facilitates the downsteam transcription of NFATC1 and activation of PLCG2. Facilitates recruitment of the transcriptional repressor PRDM1/BLIMP1 to the promoter of the anti-osteoclastogenesis gene IRF8, thereby resulting in transcription of osteoclast differentiation factors. May play a role in estrogen action.

Subunit / interactions. Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL. Interacts with PRDM1/BLIMP1; following TNFSF11/RANKL stimulation in bone marrow-derived macrophages, the interaction promotes the binding of PRDM1/BLIMP1 to the gene promoter of IRF8.

Subcellular location. Nucleus. Cytoplasm. Membrane raft.

Induction. By 17-beta-estradiol but also by a group of natural and synthetic estrogens as well as by estrogenic environmental compounds. Repressed by the antiestrogen 4-hydroxy-tamoxifen.

Similarity. Belongs to the EEIG family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5T9C2-1	1	yes
Q5T9C2-2	2
Q5T9C2-3	3

RefSeq proteins (2): NP_001030331, NP_976050 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019448	NT-C2	Domain
IPR039931	EEIG1/2-like	Family

Pfam: PF10358

UniProt features (10 total): compositionally biased region 4, region of interest 2, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T9C2-F1	69.30	0.34

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 307 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, CAIRO_HEPATOBLASTOMA_DN, GOBP_POSITIVE_REGULATION_OF_MYELOID_CELL_DIFFERENTIATION

GO Biological Process (1): positive regulation of osteoclast differentiation (GO:0045672)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), membrane raft (GO:0045121), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
positive regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane microdomain	1

Protein interactions and networks

STRING

854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EEIG1	DPM2	O94777	621
EEIG1	EPDR1	Q9UM22	609
EEIG1	PCMTD1	Q96MG8	601
EEIG1	PLEKHA7	Q6IQ23	580
EEIG1	ESR1	P03372	542
EEIG1	C10orf53	Q8N6V4	507
EEIG1	GAB2	Q9UQC2	489
EEIG1	FERMT2	Q96AC1	477
EEIG1	GLIS3	Q8NEA6	474
EEIG1	BTK	Q06187	460
EEIG1	EHBP1	Q8NDI1	450
EEIG1	NELL2	Q99435	433
EEIG1	PIP5KL1	Q5T9C9	400
EEIG1	COL11A1	P12107	399
EEIG1	BLOC1S5	Q8TDH9	377

IntAct

15 interactions, top by confidence:

A	B	Type	Score
EEIG1	SKAP1	psi-mi:“MI:0915”(physical association)	0.670
SKAP1	EEIG1	psi-mi:“MI:0915”(physical association)	0.670
EEIG1	SH3GL1	psi-mi:“MI:0915”(physical association)	0.560
ENKD1	EEIG1	psi-mi:“MI:0915”(physical association)	0.560
SH3GL1	EEIG1	psi-mi:“MI:0915”(physical association)	0.560
EEIG1	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
SERPINB8	TOX4	psi-mi:“MI:0914”(association)	0.530
EEIG1	CFTR	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): FAM102A (Two-hybrid), FAM102A (Two-hybrid), FAM102A (Two-hybrid), FAM102A (Proximity Label-MS), FAM102A (Affinity Capture-MS), FAM102A (Affinity Capture-RNA), SKAP2 (PCA), FAM102A (Two-hybrid), FAM102A (Two-hybrid), FAM102A (Two-hybrid), FAM102A (Two-hybrid), CYSRT1 (Two-hybrid), FAM102A (Affinity Capture-MS), FAM102A (Affinity Capture-MS), FAM102A (Biochemical Activity)

ESM2 similar proteins: B5DF21, B9DGG8, F4HV65, F4I5N6, O22611, P62024, P93017, Q05349, Q0P4B9, Q1PF35, Q2M3X8, Q32NP7, Q3KR53, Q3ZBW7, Q52KF3, Q52KW0, Q5F368, Q5HZ09, Q5R3Z9, Q5R8Q8, Q5R9C3, Q5RGQ8, Q5T9C2, Q5XII9, Q63HQ0, Q6DFC8, Q6GLU8, Q6NZP2, Q6PD31, Q78T81, Q86VY9, Q8BHS8, Q8BQS4, Q8C817, Q8JZM2, Q8LD26, Q8S307, Q8WWR9, Q94A43, Q9C0D0

Diamond homologs: Q5T8I3, Q5T9C2, Q6GNM6, Q78T81, Q8BQS4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

83 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1871 predictions. Top by Δscore:

Variant	Effect	Δscore
9:127944609:CCCTA:C	donor_loss	1.0000
9:127944610:CCTA:C	donor_loss	1.0000
9:127944611:CTA:C	donor_loss	1.0000
9:127944612:TA:T	donor_loss	1.0000
9:127944613:A:AT	donor_loss	1.0000
9:127944614:C:CT	donor_loss	1.0000
9:127944681:CTGT:C	acceptor_gain	1.0000
9:127944682:TGT:T	acceptor_gain	1.0000
9:127944683:GT:G	acceptor_gain	1.0000
9:127944683:GTC:G	acceptor_loss	1.0000
9:127944685:C:CC	acceptor_gain	1.0000
9:127944773:TCAC:T	donor_loss	1.0000
9:127944774:CACCC:C	donor_loss	1.0000
9:127944775:A:AC	donor_gain	1.0000
9:127944775:AC:A	donor_gain	1.0000
9:127944775:ACC:A	donor_gain	1.0000
9:127944775:ACCCT:A	donor_gain	1.0000
9:127944776:C:CC	donor_gain	1.0000
9:127944776:CC:C	donor_gain	1.0000
9:127944776:CCC:C	donor_gain	1.0000
9:127944776:CCCT:C	donor_gain	1.0000
9:127944776:CCCTC:C	donor_gain	1.0000
9:127944895:CCGC:C	acceptor_gain	1.0000
9:127944896:CGC:C	acceptor_gain	1.0000
9:127944896:CGCC:C	acceptor_gain	1.0000
9:127944899:C:CC	acceptor_gain	1.0000
9:127944899:CTG:C	acceptor_loss	1.0000
9:127944905:C:CT	acceptor_gain	1.0000
9:127944906:A:T	acceptor_gain	1.0000
9:127944910:C:CT	acceptor_gain	1.0000

AlphaMissense

2506 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:127980067:A:T	V24D	1.000
9:127950427:A:G	L137P	0.999
9:127950434:A:G	S135P	0.999
9:127950435:G:C	N134K	0.999
9:127950435:G:T	N134K	0.999
9:127950472:A:T	L122H	0.999
9:127953809:C:G	R88P	0.999
9:127953810:G:T	R88S	0.999
9:127953895:C:A	W59C	0.999
9:127953895:C:G	W59C	0.999
9:127953897:A:G	W59R	0.999
9:127953897:A:T	W59R	0.999
9:127980076:A:G	L21P	0.999
9:127980102:G:C	F12L	0.999
9:127980102:G:T	F12L	0.999
9:127980103:A:G	F12S	0.999
9:127980104:A:G	F12L	0.999
9:127948373:G:C	F152L	0.998
9:127948373:G:T	F152L	0.998
9:127948375:A:G	F152L	0.998
9:127950427:A:T	L137H	0.998
9:127950433:G:A	S135F	0.998
9:127950446:G:T	R131S	0.998
9:127950472:A:G	L122P	0.998
9:127950531:G:C	F102L	0.998
9:127950531:G:T	F102L	0.998
9:127950533:A:G	F102L	0.998
9:127950536:C:G	G101R	0.998
9:127953575:C:A	K99N	0.998
9:127953575:C:G	K99N	0.998

dbSNP variants (sampled 300 via entrez): RS1000088271 (9:127941245 T>C), RS1000166791 (9:127976645 T>C), RS1000167045 (9:127941066 T>C), RS1000327857 (9:127973500 A>G), RS1000369572 (9:127957943 G>A,T), RS1000377602 (9:127974323 G>A), RS1000378180 (9:127956216 T>C), RS1000566049 (9:127942106 C>A,T), RS1000569866 (9:127945244 G>A), RS1000584170 (9:127950317 G>A,T), RS1000590995 (9:127981975 G>A), RS1000677137 (9:127962752 G>T), RS1000699601 (9:127978595 CA>C), RS1000773454 (9:127975144 T>C), RS1000892418 (9:127969162 G>A)

Disease associations

OMIM: gene MIM:610891 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003467_6	Glaucoma (primary angle closure)	8.000000e-12
GCST003467_7	Glaucoma (primary angle closure)	5.000000e-11
GCST005951_65	Body mass index	5.000000e-09
GCST005977_23	Monocyte count	2.000000e-10
GCST005987_46	Albumin-globulin ratio	3.000000e-08
GCST008971_1	Urate levels	3.000000e-11
GCST008972_77	Urate levels	4.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0005091	monocyte count
EFO:0005128	albumin:globulin ratio measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

53 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, decreases reaction	4
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol A	decreases expression	1
quercitrin	increases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	decreases reaction, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
gamma-sitosterol	increases expression	1
ferrous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
ciglitazone	increases expression, affects binding	1
4-nonylphenol	increases expression	1
4-octylphenol	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	increases expression	1
Rosiglitazone	increases expression	1
Temozolomide	decreases expression	1
Fulvestrant	decreases reaction, increases expression	1
Ethanol	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.